study to assess the efficacy and safety of atuliflapon in moderate-to-severe uncontrolled asthma

Conditions: Asthma

Summary: this is a randomised, placebo-controlled, double-blind study to assess the efficacy and safety of atuliflapon administered once daily over a 12-week treatment period to adult participants with moderate to severe uncontrolled asthma.

the study will enroll participants with moderate to severe uncontrolled asthma who are on low-dose inhaled corticosteroid (ics) - a long-acting beta-agonist (laba) or medium-to-high-dose ics with or without laba background treatment. the study will be initiated by lead-in pharmacokinetics (pk) cohort in asthma participants. participant will be randomised globally, including participants in lead-in pk cohort (2 arms) and in part 1 of the study (2 arms). in the lead-in pk cohort, participants will be randomised to atuliflapon or placebo (recruitment completed). in part 1 of the study, participants will be stratified by geographical region, and grouped based on high or low levels of biomarker at screening (visit 1).

Eligibility criteria:
inclusion criteria lead-in pk cohort: * 18 to 55 years of age inclusive at the time of signing the informed consent at screening visit 1. * bodyweight 50 to 120 kg (inclusive) and bmi 18 to 32 kg/m\^2 (inclusive) at screening visit 1. * documented asthma diagnosis ≥12 months prior to screening visit 1. * able to perform acceptable lung function testing for fev1 according to american thoracic society / european respiratory society (ats/ers) 2019 acceptability criteria. * morning pre- bronchodilator (bd) forced expiratory volume (fev)1 ≥ 40% predicted at screening visit 1 and visit 2. * treated with low dose inhaled corticosteroid plus long-acting β2-agonist (ics-laba) or medium-high dose ics alone or in combination with laba at a stable dose for at least 3 months prior to screening visit 1. also, treatment with additional asthma controller therapies (eg, lama) at a stable dose ≥ 3 months prior to screening visit 1 is allowed. * participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to visit 2. general inclusion criteria for part 1: * body weight ≥ 40 kg and body mass index (bmi) \< 35 kg/m\^2. * documented history of ≥ 1 severe asthma exacerbation within 1 year prior to screening visit 1. * able to perform acceptable lung function testing for fev1 according to ats/ers 2019 acceptability criteria. * morning pre-bd fev1 between ≥ 40% and ≤ 85% predicted at screening visit 1 and visit 3. * an asthma control questionnaire (acq)-6 score ≥ 1.5 at screening visit 1 and at visit 3. exclusion criteria * a severe asthma exacerbation within 8 weeks of screening (visit 1) or within 12 weeks of randomisation (visit 3). * a positive test result of an approved antigen test (confirmed by a positive rt-pcr test) or a positive rt-pcr test for sars-cov-2, the virus responsible for covid-19, at screening visit 1 or at visit 2 for the pk lead-in cohort. for part 1 the testing will be done at visit 3. results from the mandatory tests at visit 2 (pk lead-in cohort) and visit 3 (part 1) must not be older than 48 hours and must be available before randomisation. * participants with a significant covid-19 illness within 6 months of enrolment. * clinically important pulmonary disease other than asthma. * any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable. * any clinically significant cardiac disease. * history of severe renal disease or history of creatinine clearance \< 30 ml/min × m2 calculated using cockcroft-gault equation. * severe hepatic impairment (child-pugh class c). * previous hepatotoxicity related to zileuton or leukotriene receptor antagonist (ltras) (eg montelukast). * participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for hepatitis b, hepatitis c, or human immunodeficiency virus (hiv). * evidence of active tuberculosis (tb), either treated or untreated or latent tb. * current or history of alcohol or drug abuse (including marijuana). * current diagnosis of cancer, not including in-situ or non-melanoma skin cancer or other previous malignancies where curative therapy was completed at least 5 years prior to screening visit 1. * clinically important ongoing or previous psychiatric disease, especially suicidal behaviour, that in the opinion of the investigator might compromise the safety of the participant in the study. * treatment with any serum creatinine-altering drugs within 1 month prior to screening visit 1 including but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins. * treatment with systemic corticosteroid use within 8 weeks (oral) or 12 weeks (intramuscular) before screening (visit 1) or 12 weeks (oral) or 16 weeks (im) before randomization (visit 3). * treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, and dupilumab within 6 months of screening visit 1 or 5 half-lives whichever is longer. * treatment with 5-lipoxygenase inhibitors (eg zileuton or other 5-lo inhibiting supplements) within 6 weeks prior to visit 0 and within 8 weeks prior to visit 1).treatment with ltras (eg, montelukast) within 2 weeks prior to visit 0 and within 4 weeks prior to screening visit 1. * inhaled corticosteroid + fast-acting β2 agonist as a reliever (eg symbicort or fostair maintenance and reliever treatment) is not allowed 15 days prior to screening visit 1, during screening (visit 1)/run-in and the treatment period and preferably 1 week after the last dose of study intervention. * live or attenuated vaccines within 4 weeks of screening visit 1. * immunoglobulin or blood products within 4 weeks of screening visit 1. * treatment with gemfibrozil within 4 weeks of screening visit 1. * any immunotherapy within 6 months of screening visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to screening visit 1 and expected to continue through to the end of the follow-up period. * potent inducers/inhibitors of cytochrome p450 3a4 within 4 weeks of screening visit 1. * treatment with simvastatin, lovastatin, and atorvastatin at doses \> 40 mg per day within 1 month prior to screening visit 1. treatment with sensitive cytochrome 3a substrates with narrow therapeutic window should be avoided from randomization to study drug. * for female participants on ethinyl oestradiol containing combined oral contraceptives, the ethinyl oestradiol doses exceeding 20 mcg per day. * concurrent enrolment in another clinical study. * previous participation in the current clinical study. * participant treated with any investigational drug within 4 months prior to screening visit 1. * known history of allergy or reaction to any component of the study intervention formulation. * smokers with smoking history of \< 10 pack-years or users of vaping or e-cigarettes, must have stopped at least 6 months prior to screening visit 1. * involvement in the planning and/or conduct of the study. * donation of blood (≥ 450 ml) within 3 months or donation of plasma within 14 days before screening visit 1. * major surgery within 8 weeks prior to screening visit 1, or planned inpatient surgery, major dental procedure or hospitalisation during the screening (visit 1), treatment or follow-up periods.

Keywords: efficacy safety multiple dose levels adults